# NM_022437.3(ABCG8):c.144G>A (p.Glu48=)

https://sugi.bio/variant/abcg8-p-glu48

## Summary

**ABCG8 p.Glu48= (c.144G>A)** is classified **Uncertain significance** in ABCG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-30). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1668682396 · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the ABCG8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCG8](https://sugi.bio/atlas/gene/ABCG8/) |
| Protein change (HGVS p.) | p.Glu48= |
| Coding change (HGVS c.) | c.144G>A |
| MANE Select transcript | [NM_022437](https://www.ncbi.nlm.nih.gov/nuccore/NM_022437) |
| dbSNP | [rs1668682396](https://www.ncbi.nlm.nih.gov/snp/rs1668682396/) |
| Variant type | single nucleotide variant |
| Location | chr2:43844587-43844587 (GRCh38) |
| ClinVar | [VCV2810817](https://www.ncbi.nlm.nih.gov/clinvar/variation/2810817/) |

**All HGVS expressions:** `LRG_1182:g.17646G>A`, `LRG_1182t1:c.144G>A`, `NC_000002.11:g.44071726G>A`, `NC_000002.12:g.43844587G>A`, `NG_008884.2:g.17646G>A`, `NM_001357321.2:c.144G>A`, `NM_022437.3:c.144G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.17, GERP -0.425, phastCons 1 — weakly conserved position
- CADD: **PHRED 3.748**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · 1/6,062 in the highest group · 1/1,461,756 alleles overall — ultra-rare (popmax 0.0165%, mid).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ABCG8** population constraint: LOEUF 1.329, pLI 5.1931e-31, missense-Z -2.6097; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **sitosterolemia** — Definitive (AR)

## Protein context {#protein}

Residue **48** lies in the abc transporter domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 80.94, 39% of residues very-high.

**8 experimental structure(s)** (PDB): [5DO7](https://www.rcsb.org/structure/5DO7), [7JR7](https://www.rcsb.org/structure/7JR7), [7R87](https://www.rcsb.org/structure/7R87), [7R88](https://www.rcsb.org/structure/7R88), [7R89](https://www.rcsb.org/structure/7R89), [7R8A](https://www.rcsb.org/structure/7R8A).

## What this gene does {#gene-function}

*Describes the biological roles of ABCG8 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ABCG8's established molecular role includes ATPase-coupled transmembrane transporter activity. p.Glu48= falls in the abc transporter domain. In Reactome, ABCG8 is annotated in disease pathway(s) including **Defective ABCG5 causes sitosterolemia**, **Defective ABCG8 causes GBD4 and sitosterolemia**.

**Disease mechanism (Reactome):** ABCG8 loss or alteration is curated in [Defective ABCG5 causes sitosterolemia](https://reactome.org/content/detail/R-HSA-5679096), [Defective ABCG8 causes GBD4 and sitosterolemia](https://reactome.org/content/detail/R-HSA-5679090).

### Pathways affected {#pathways}

ABCG8 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCG5 causes sitosterolemia](https://reactome.org/content/detail/R-HSA-5679096) | curated |
| ⚕ [Defective ABCG8 causes GBD4 and sitosterolemia](https://reactome.org/content/detail/R-HSA-5679090) | curated |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ATPase-coupled transmembrane transporter activity, protein heterodimerization activity.

**Biological process:** negative regulation of intestinal phytosterol absorption, cholesterol efflux, cholesterol homeostasis, negative regulation of intestinal cholesterol absorption.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-30.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-30 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ABCG8 variant pages (same residue, condition, or type): [ABCG8 c.64-2A>G](/variant/abcg8-c-64-minus-2a-g), [ABCG8 c.964+1G>T](/variant/abcg8-c-964-plus-1g-t), [ABCG8 c.965-1G>C](/variant/abcg8-c-965-minus-1g-c), [ABCG8 p.Arg121Ter](/variant/abcg8-p-arg121ter), [ABCG8 p.Arg164Ter](/variant/abcg8-p-arg164ter), [ABCG8 p.Arg405Cys](/variant/abcg8-p-arg405cys), [ABCG8 p.Arg412Ter](/variant/abcg8-p-arg412ter), [ABCG8 p.Gln271Ter](/variant/abcg8-p-gln271ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2810817). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*